Cellular redox: a modulator of intestinal epithelial cell proliferation.

issue oxidative stress, which results from a disturbance in the cellular prooxidant-antioxidant balance in favor of prooxidants, is an important contributor to the genesis of gut pathologies such as inflammation and cancer (1). That hydroperoxy and hydroxy fatty acids can provoke colonic DNA synthesis and induction of ornithine decarboxylase (3) is consistent with stimulation of proliferative responses associated with oxidant challenge and underscores the tumorigenic potential of these reactive species. This consideration is pertinent to the intestine, whose epithelium often encounters oxi-dants like lipid peroxides of dietary or endogenous origin. Because oxidative stress induces changes in cellular oxidation reduction (redox) events, these findings highlight a role for redox in the control of intestinal epithelial proliferative activity. The current review will focus on the concepts salient to understanding control of cellular redox homeostasis, the relationship between cellular redox and cell proliferation, and how a loss of this redox balance alters intestinal cell prolifer-ative responses. This knowledge underpins the centrality of cellular redox in governing cell growth. Glutathione and thiol redox balance. The tripeptide glu-tathione (known as J-glutamylcysteinylglycine or GSH) is the major low-molecular-weight thiol in cells that controls cellular thiol-disulfide redox state, which is essential for normal redox signaling (9). The dynamics of cellular redox balance are achieved by maintenance of the thiol-to-disulfide status of reduced GSH and its oxidized form, GSSG. Oxidation-reduction and thiol-disulfide exchange reactions during oxidative perturbations will cause a redistribution of GSH and GSSG; the resultant quantitative shift in the ratio of GSH to GSSG in favor of GSSG directly reflects an oxidized redox status and is a convenient expression of oxidative stress within a cell. The redox potential (E h), which takes into consideration the stoi-chiometry of two GSH oxidized per GSSG formed, is another useful quantitative expression for the redox state of the GSH/GSSG pool. E h is calculated by the Nernst equation: E h = E o + (RT/nF)ln([GSSG]/[GSH] 2) (9) (where E o is the standard potential for the redox couple at defined pH, R is the gas constant , T is the absolute temperature, F is Faraday's constant, and n is the number of electrons transferred), and cellular estimates of E h for the GSH/GSSG redox couple are in the range of 260 to 200 mV. During oxidative stress, intracellular GSSG accumulates (Fig. 1), and the loss of thiol redox balance will elicit deleterious consequences for metabolic regulation, cellular integrity, and organ …